U.S. patent number 4,882,335 [Application Number 07/205,758] was granted by the patent office on 1989-11-21 for method for treating alcohol-drinking response.
This patent grant is currently assigned to Alko Limited. Invention is credited to John D. Sinclair.
United States Patent |
4,882,335 |
Sinclair |
November 21, 1989 |
Method for treating alcohol-drinking response
Abstract
A therapeutic method is provided for use as an adjunct in the
treatment of alcoholism. The method consists of extinguishing the
alcohol-drinking response of alcoholics during a relatively short
period of time by having them drink alcoholic beverage repeatedly
while an opiate antagonist blocks the positive reinforcement
effects of ethanol in the brain.
Inventors: |
Sinclair; John D. (Espoo,
FI) |
Assignee: |
Alko Limited (Helsinki,
FI)
|
Family
ID: |
22763531 |
Appl.
No.: |
07/205,758 |
Filed: |
June 13, 1988 |
Current U.S.
Class: |
514/282;
514/811 |
Current CPC
Class: |
A61K
31/00 (20130101); A61K 31/485 (20130101); Y10S
514/811 (20130101) |
Current International
Class: |
A61K
31/00 (20060101); A61K 31/485 (20060101); A61K
031/44 () |
Field of
Search: |
;514/810,811,812,282 |
Other References
Chem. Abst., 106-12821P, (1987). .
"Naloxone Persistently Modifies Water-Intake", Pharmacology
Biochemistry & Behavior, Mar. 25, 1986, vol. 29, pp. 331-334.
.
"Feasibility of Effective Psychopharmacological Treatments for
Alcoholism", J. D. Sinclair, Ph.D, British Journal of Addition,
1987, 82, 1213-1223..
|
Primary Examiner: Friedman; Stanley J.
Attorney, Agent or Firm: Armstrong, Nikaido, Marmelstein,
Kubovcik & Murray
Claims
I claim:
1. A method for treating alcoholism by extinguishing the
alcohol-drinking response, comprising the steps of:
repeatedly administering to a subject suffering from alcoholism, an
opiate antagonists selected from the group consisting of naloxone,
naltrexone, cyclazocine, diprenorphine, etazocine, levalorphan,
metazocine, nalorphine and salts thereof in a daily dosage
sufficient to block the stimulatory effect of alcohol;
while the amount of antagonist in the subject's body is sufficient
to block the stimulatory effect of alcohol, having the subject
drink an alcoholic beverage; and
continuing the steps of administration of the opiate antagonist and
drinking of an alcoholic beverage until the alcohol-drinking
response is extinguished.
2. The method of claim 1 further comprising the step of punishing
the patient after the alcoholic beverage is consumed, said step of
punishment being selected from the group consisting of
administration of electric shock, administration of emetics, and
administration of an alcohol sensitizing compound.
3. The method of claim 2 wherein the alcohol sensitizing compound
is disulfiram or cyanamide.
4. The method of claim 1 further comprising continuing the
administration of an opiate antagonist after the alcohol-drinking
response is extinguished.
5. The method in accordance with claim 1 wherein the opiate
antagonist is naloxone.
6. The method in accordance with claim 5 wherein the dose of
naloxone is from 0.2 to 30 mg daily.
7. The method in accordance with claim 1 wherein the opiate
antagonist is naltrexone.
8. The method in accordance with claim 7 wherein the dose of
naltrexone is from 20 to 300 mg daily.
Description
FIELD OF THE INVENTION
The invention is a treatment for alcohol abuse in which the
alcohol-drinking response is extinguished over a limited number of
sessions by being emitted while the reinforcement from alcohol is
blocked with an opiate antagonist such as naloxone or
naltrexone.
BACKGROUND OF THE INVENTION
Alcoholism is the most costly health problem in many countries. The
cost, e.g., in America is estimated to be about $117,000,000,000
per year. The treatment methods currently used are not very
effective. Most alcoholics drop out of treatment within a month or
two. Few alcoholics, regardless of the type of treatment, are able
to avoid relapses and renewed alcohol abuse.
No one is born an alcoholic. The drinking of alcohol (ethanol or
ethyl alcohol) is a learned response, reinforced largely by the
rewarding effects of alcohol in the central nervous system--the
euphoria from lower, stimulatory doses of ethanol. An alcoholic is
a person who, through an interplay of genetic and environmental
factors, has had the alcohol-drinking response reinforced so often
and so well that it becomes too strong for the individual to
continue functioning properly in society. The strong
alcohol-drinking response--i.e., the drive for alcohol--then
dominates the person's behavior and life.
The current methods for treating alcoholism are not very successful
probably because they do not effectively weaken the alcoholic's
alcohol-drinking response. Some methods (e.g., counselling,
Alcoholics Anonymous) are aimed at increasing the alcoholic's
ability or will power to withstand the drive for alcohol. The
drive, however, is not weakened and the patient is told that he
will remain an alcoholic, that is, a person with an overly strong
alcohol-drinking response, for the rest of his life. These methods
succeed in some alcoholics, but in most the time eventually comes
when a momentary decrease in will power causes a resumption of
alcohol drinking and alcohol abuse.
Other treatments use punishment of various sorts (e.g., electric
shock, disulfiram reactions, loss of a job) to try to stop alcohol
drinking. Punishment is, however, a poor method for changing
behavior and has many limitations. In particular, it is ineffective
when positive reinforcement is still being received for the same
response that is punished. Since the treatments that punish alcohol
drinking do not block the positive reinforcement of the same
response coming from alcohol in the brain, they should not be
expected to be very effective.
A third type of treatment has been proposed. Alcohol and opiates
appear to cause positive reinforcement largely through the same
neuronal system in the brain. Consequently, opiates such as
morphine or methadone might be able to satisfy the drive for
alcohol and thus abolish alcohol drinking. This does indeed occur
in rats and other animals, and there is evidence suggesting opiates
could also succeed in making alcoholics stop drinking alcohol. The
treatment probably would, however, turn alcoholics into opiate
addicts, which is, of course, not a good solution.
Instead of counteracting the drive for alcohol or temporarily
satisfying it, a successful treatment for alcoholics should
permanently weaken the alcohol-drinking response. Fortunately,
there is a well-established method for weakening a learned
response: "extinction". Extinction consists of having the response
emitted repeatedly in the absence of positive reinforcement.
It is relatively simple to remove external sources of positive
reinforcement, such as the food a rat gets for pressing a lever or
even the social reinforcement a person sometimes gets for drinking
alcohol. But much of the positive reinforcement for alcohol
drinking is internal, from the rewarding effects of alcohol in the
brain.
The results showing that alcohol and opiates share a common
mechanism of reinforcement show how the internal positive
reinforcement from alcohol might be blocked. Various substances,
called opiate antagonists, are able to block the receptors for
opiates and thus prevent the effects of, e.g. morphine.
Furthermore, there is already evidence that the two most commonly
used opiate antagonists, naloxone and naltrexone, do block positive
reinforcement from alcohol. First, they block the stimulatory
effect of alcohol which is generally thought to be related to the
euphoria and positive reinforcement. Second, it has been shown that
while they are in the body they reduce voluntary alcohol drinking
and intragastric self-administration of alcohol by animals.
Naloxone and naltrexone were originally intended for use in
treating overdoses of opiates. They have since been suggested for
use against a wide variety of problems including respiratory
failure, anorexia nervosa, bulimia, obesity, emesis and nausea,
shock, severe itching, constipation, growth of neoplasms, and
sexual impotence and frigidity. There have been many studies
attempting to use naloxone to reverse alcohol intoxication and
especially the coma produced by very large amounts of alcohol;
although the results have been mixed and there is still controversy
as to whether naloxone can antagonize severe alcohol intoxication,
it is important to note that none of these studies reported any bad
effects from giving naloxone in conjunction with alcohol. The doses
of naloxone have ranged between about 0.2 and 30 mg daily, and
naltrexone from about 20 to 300 mg daily. Other suggested uses are
for the opiate antagonists in conjunction with other drugs,
particularly, opiate agonists. For instance, U.S. Pat. No.
3,966,940 is for a compound containing narcotics or analgesics plus
naloxone to be given especially to narcotic addicts. In these cases
the opiate or other drug is seen to be active pharmacological agent
and the opiate antagonist is included to counteract some of its
effects.
Continual treatment with opiate antagonists should reduce the
alcohol intake of alcoholics: so long as the antagonist is in the
body, the alcoholic should have little incentive for drinking
because alcohol is not rewarding. This maintenance treatment,
however, has the same problem found with other long-term deterrent
treatments, such as that with disulfiram: how to keep the alcoholic
on the medication. Since there is still a strong drive for alcohol,
the alcoholic is likely to drop out of treatment and stop taking
the antagonist so that he or she can satisfy the drive by drinking
again.
However, combining the well-established procedure of extinction
from psychology with the pharmacological findings that opiate
antagonists block reinforcement from alcohol provides a new and
much more promising way of treating alcoholism. Indeed, it provides
what could be called the first true cure for alcoholism. After a
relatively short period of treatment during which an opiate
antagonist is employed in extinction therapy, the patient is no
longer an alcoholic, because the overly-strong alcohol-drinking
response that made the patient be an alcoholic is extinguished. The
method for using this extinction procedure is the present
invention.
The idea of using extinction therapy with an opiate antagonists for
alcoholics has not been suggested previously. A similar idea with
naltrexone has, however, been suggested for opiate addicts (see P.
F. Renault, NIDA Research Monograph No. 28, pp. 11-22, 1981), but
extinction was not included in the design of the clinical tests.
The patients were simply detoxified, given naltrexone or placebo,
and released. There was no program for encouraging them to take
opiates while under the influence of naltrexone, as required for
extinction. Consequently, the general result was what would likely
happen also with such a naltrexone maintenance program with
alcoholics: a very large percentage of the addicts dropped out,
stopped taking naltrexone, and started taking opiates again. Of the
total of 1005 subjects, however, "17 of the naltrexone and 18 of
the placebo subjects actually tested the blockade by using an
opiate agonist" when naltrexone would have been active, and "in
this subsample, the naltrexone patients had significantly fewer
subsequent urines positive for methadone or morphine . . . The
pattern in the naltrexone group was to test once or twice with
heroin or methadone and then to stop. The use of these drugs in the
placebo group was sporadic during the entire course of treatment .
. . [Also, on an analog craving scale] the naltrexone patients
reported significantly less craving toward the end of their
evaluation than did the placebo-treated patients."
These results suggest that naltrexone would be much more useful
against opiate addiction if the addicts were given extinction
sessions in which they were encouraged to use narcotics while the
positive reinforcement was blocked. Furthermore, in relation to the
present invention, by showing the extinction therapy with
naltrexone does work in humans, they support the hypothesis that it
would reduce alcohol abuse and the craving for alcohol in
alcoholics.
The example included here shows that the extinction procedure
progressively decreases and eventually almost abolishes alcohol
drinking by rats and that alcohol intake remains reduced long after
all naloxone should have been removed from the body. The high
predictive validity of this animal model for indicating treatments
that affect human alcohol consumption is discussed in Sinclair,
British Journal of Addiction 82, 1213-1223 (1987).
SUMMARY OF THE INVENTION
The present invention contemplates a therapeutic method, utilizing
the ability of opiate antagonists to block the positive
reinforcement from alcohol, to extinguish the alcohol-drinking
response of alcoholics. The extinction program consists of numerous
sessions in which the alcoholic has an opiate antagonist
administered and then drinks alcohol.
The extinction procedure abolishes the alcoholic's strong
alcohol-drinking response. Optimally, the patient's drive for
alcohol is returned to the level present before he or she ever
tasted alcohol. Thus, by definition, the patient is no longer an
alcoholic.
Admittedly, the patient can relearn the alcohol-drinking response
and become an alcoholic again, and relearning a response that has
been extinguished occurs more rapidly than the initial acquisition.
But with the first-hand knowledge of the consequences of the first
acquisition of alcoholism, and with even a moderate level of will
power and outside support, most alcoholics will avoid making the
same mistake twice.
This extinction procedure is a useful adjunct for various other
methods of treating alcoholics, including punishment of alcohol
drinking, procedures to improve will power and social
rehabilitation, and maintenance procedures for preventing renewed
use of alcohol. These other methods have previously been very
limited because of the continuing high drive for alcohol, but they
should be much more effective once the alcohol-drinking response
has been extinguished.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the apparent extinction of alcohol drinking in Long
Evans and AA rats caused by 4 daily sessions of drinking alcohol
after administration of naloxone (mean.+-.standard error).
FIG. 2 shows the apparent extinction of alcohol drinking in Wistar
rats caused by 4 daily sessions when naloxone was administered 5
minutes before the hour of drinking alcohol ("paired naloxone"
group) and the lack of effect of naloxone injected each day 3 hours
after alcohol drinking ("unpaired naloxone" group).
FIG. 3 shows the continued reduction in alcohol drinking by the
Long Evans rats that had previously undergone extinction (see FIG.
1) relative to their controls. No naloxone was administered during
this time, but the rats treated before with naloxone drank
significantly less than the controls on each of the first 7 days.
They eventually returned to the control level, apparently because
they were not made to abstain completely, did drink some alcohol,
and thus relearned the alcohol-drinking response.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The extinction procedure can be used in all individuals classified
by any of various means as alcoholics or alcohol abusers, except
those in which the administration of an opiate antagonist is
contraindicated and those suffering from Korsakoff's syndrome. (The
extinction procedure would probably work poorly in patients with
Korsakoff's syndrome.)
The patients can be interviewed to determine the alcoholic
beverages they usually drink and the drinking situations in which
they normally imbibe. They can then be informed that unlike most
treatments, this one does not involve immediately becoming
abstinent; instead, their alcohol drinking is to be slowly
diminished over many days and only after that will they have to
abstain. This procedure should also help to reduce the severity of
withdrawal symptoms that are often produced by abrupt termination
of alcohol intake.
The patient can then have an opiate antagonist administered shortly
before beginning to drink an alcoholic beverage. Examples of opiate
antagonists are naloxone, naltrexone, cyclazocine, diprenorphine,
etazocine, levalorphan, metazocine, nalorphine, and their salts.
The preferred opiate antagonists are naloxone and naltrexone, both
of which have been approved for use in humans and have been shown
to be free of severe side-effects. Neither is addicting or habit
forming. The preferred dose range for naloxone is 0.4 to 10 mg
daily if taken by injection; the dose would have to be much larger
if it were taken orally. The preferred dose range for naltrexone is
50 to 200 mg daily. The dose administered in a specific case will
depend upon the age and weight of the patient, the frequency of
administration, and the route of administration, but must be
sufficient to assure that the antagonist will be present in
sufficient quantities in the body throughout the entire evening of
alcohol drinking. The antagonist could be administered in such a
way that it is continually present in the body throughout the weeks
of extinction therapy. Administration in a way that allows the
patient to be free of pharmacologically-active quantities of the
antagonist during the following day may be preferred, since it
allows the alcoholic to eat food and drink non-alcoholic beverages
during the daytime without interference from the antagonist. In the
latter case, the patient will be under strict orders to confine all
alcohol drinking to the evening hours after the antagonist has been
administered.
Examples of routes of administration for the antagonist are
injection, oral consumption in any form, transdermal
administration, slow-release injection, nasal administration,
sublingual administration, implantable drug delivery depots, and
the like. A non-obtrusive, non-painful route would be
preferred.
The first extinction session (i.e., drinking after administration
of the antagonist) can be conducted under close supervision in the
treatment center. It is important that later extinction sessions be
conducted in the same drinking situations and with the same
alcoholic beverages that the patient usually has employed in the
past. The stimuli from these specific beverages and situations help
to elicit somewhat separate alcohol-drinking responses for the
individual. For example, in a particular alcoholic, the
alcohol-drinking response of having beers while watching a game on
TV may be at least partly independent of his responses of imbibing
cocktails at a party or drinking whiskey at a bar. Each should be
extinguished in order to assure the generality of the treatment.
Although the alcoholic should be encouraged to drink alcohol in the
extinction sessions, there should be no social reinforcement for
doing so.
The number of extinction sessions required for each patient will
depend upon the severity of his or her alcoholism and the number of
specific drinking situations in which the alcohol-drinking response
must be extinguished. The duration of the extinction program may
therefore range from about 1 to 5 weeks.
Once the alcohol-drinking response has been sufficiently weakened,
the final extinction sessions could be conducted along with an
element of punishment. Examples of punishment include mild electric
shock when the alcohol is consumed, production of conditioned taste
aversion from very large doses of alcohol with or without emetics,
aversion therapy with an alcohol-sensitizing compound such as
disulfiram or cyanamide, and the like.
After the final extinction session, the patient is told to abstain
from all alcohol in the future. Various procedures can then be used
to help ensure that the patient does in fact refrain from drinking
alcohol. Such procedures include counselling, psychotherapy, family
therapy, job therapy, joining Alcoholics Anonymous and the like.
Efforts should also be taken to help the patient resume a normal
productive life.
The patient should also be informed that although his or her
alcohol-drinking response has been extinguished in the most
frequently used drinking situations, it is possible that some have
been missed. Consequently, if the patient anticipates or is
experiencing a situation in which the response has not been
extinguished, he or she should request additional extinction
sessions involving this new situation. Alternatively, the patient
could be kept on a maintenance program with continued
administration of the opiate antagonist.
The present invention is further illustrated by the following
example.
EXAMPLE
Extinction of alcohol drinking in 3 strains of rats
Methods
The effects of drinking alcohol after being injected with naloxone
was studied in male rats of the AA strain developed for very high
levels of alcohol drinking by selective breeding, in male Long
Evans rats, and in male Wistar rats. In each case the animals first
had several weeks of continual access to 10% (v/v) ethanol, plus
food and water, during which time their alcohol drinking increased
rapidly at first and eventually, after 3 to 4 weeks, approached a
stable asymptotic level. They were then switched to having access
to 10% alcohol for only 1 hour each day. After alcohol consumption
had stabilized, the rats of each strain were divided into groups
matched for alcohol consumption during the last week of 1 hour
daily access. One group in each strain was then injected with 10
mg/kg naloxone hydrochloride 5 minutes before their hour of alcohol
access for the next 4 days and a control group was injected with a
similar volume of saline. There was a third group ("unpaired
naloxone") of Wistar rats that was injected with 10 mg/kg of
naloxone 3 hours after the end of their hour of alcohol access. The
alcohol drinking during 1 hour on the day after the last injection
was also recorded. The Long Evans rats were then switched back to
continual access to alcohol and their intake measured for the next
13 days.
Results
Administering naloxone before providing access to alcohol
progressively decreased alcohol drinking in all 3 strains (FIGS. 1
and 2). By the fourth day it was almost abolished in each strain,
and the alcohol intake was significantly (p<0.05) lower than
both the "pre" level (during the preceding week) and the level
after the first naloxone injection. The saline controls tended to
increase their alcohol intake across days, perhaps due to the
stress of injection, and drank significantly more alcohol than the
rats given naloxone before alcohol on at least the last 3
extinction days and on the "post" day, 24 hours after the last
injection.
The subsequent alcohol drinking by the Long Evans rats is shown in
FIG. 3. The rats subjected to extinction with naloxone continued to
drink significantly less alcohol than their saline controls on each
day of the first week and then gradually returned to the control
level. The latter is probably the result of relearning the
alcohol-drinking response. Consistent with the common finding that
a response is reacquired after extinction more rapidly than it is
initially acquired, they took less than 2 weeks to reacquire the
response, whereas naive Long Evans rats (i.e., ones that have never
had alcohol before) require 3 to 4 weeks to reach this level of
alcohol intake.
The Wistar rats given naloxone 3 hours after alcohol drinking
("unpaired naloxone") did not differ significantly from the
controls at any time (FIG. 2); their slightly lower intake can
probably be attributed to the fact that, unlike the controls, they
were not stressed by injection immediately before having access to
alcohol. The "unpaired naloxone" group drank significantly more
alcohol than the "paired naloxone" group on each of the 4
extinction days. This suggests that the reduction in alcohol
drinking was caused specifically by the experience acquired while
naloxone was paired with alcohol drinking.
These results are all consistent with the hypothesis that consuming
alcohol while naloxone is present causes the alcohol-drinking
response to be extinguished. Water intake and body weight were not
reduced and there were no indications of any effects detrimental to
the health of the animals.
* * * * *